HYDIN基因突变在云南地区散发先天性房间隔缺损发生中的作用机制研究

Congenital heart disease (CHD) seriously endangered the health care systems. Sporadic atrial septal defects (ASD) is the most common subtype of CHD. In our previous studies, we observed patients with ASD had higher mutation frequency of HYDIN gene locus 71098693 in Yunnan province, the migration and proliferation ability of myocardial cell were reduced and apoptosis was increased after knock down HYDIN gene. But the mechanism of HYDIN gene in the ASD is unclear. According to reports in the literature, the cilia dysfunction plays a central role in CHD, mitochondria play an important role in the cilia dysfunction, and HYDIN gene mutations can lead to the cilia dysfunction through the loss of cilia C2b gene wire core tube structure. Therefore, we hypothesize that HYDIN gene mutations may be involved in the incidence of ASD by regulating the mitochondria and cilia function of myocardial cell. In this study, we aim to further characterize the role of the HYDIN gene mutations in the pathogenesis of sporadic atrial septal defects in Yunnan. We will focuses on the effect of HYDIN gene mutations on the mitochondria and cilia function of myocardial cell by the three levels of ASD clinical samples, cells and rat model. Our results will uncover the mechanism of HYDIN gene mutations during the progression of ASD, and will help with molecular markers of prenatal screening and early therapeutic interventions of this disease.

先天性心脏病（CHD）严重危害人类健康，散发房间隔缺损（ASD）是最常见的CHD亚型。我们前期研究发现：HYDIN基因71098693位点突变频率在云南省散发ASD患者中显著增高；敲降HYDIN基因后心肌细胞迁移和增殖能力降低，凋亡增加。但HYDIN基因在ASD中的作用机制尚不明确。据文献报道，纤毛功能障碍在CHD的发生中起核心作用，线粒体在纤毛功能障碍中发挥重要调控作用，而HYDIN基因突变可引起纤毛基因丝中心微管C2b结构缺失，导致纤毛功能障碍。因此，我们推测HYDIN基因突变可能通过调控心肌细胞线粒体和纤毛功能参与ASD的发生。本项目拟在前期工作的基础上，通过ASD临床样本、细胞和大鼠模型三个层次开展研究，集中分析HYDIN基因突变对心肌细胞线粒体和纤毛功能的影响并由此导致ASD的分子作用机制，为ASD产前筛查分子标记和早期干预靶点的探寻提供理论依据。